Highly homologous miR-135a and miR-135b converting non-small cell lung cancer from suppression to progression via enhancer switching.

IF 3.1 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Kaicheng Zhou, Wenxuan Li, Lu Chen, Siyue Chen, Mengxing Liu, Zhicong Yang, Zhanrui Mao, Wenqiang Yu
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引用次数: 0

Abstract

microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles. Using non-small cell lung cancer (NSCLC) as a paradigm, our findings unveiled the downregulation of miR-135a-5p and upregulation of miR-135b-5p within NSCLC through TCGA database. Consequently, we further investigated their functional differences in A549 cells. Overexpression of miR-135b-5p enhanced the proliferation and migration capabilities of A549 cells, whereas miR-135a-5p transfection exhibited the opposite effect. We demonstrated that the activation of specific enhancers serves as a crucial mechanism underlying the disparate functions exerted by miR-135a-5p and miR-135b-5p in the context of NSCLC, consequently instigating a shift from inhibition to activation in NSCLC progression. Finally, we validated through animal experiments that miR-135b-5p promoted tumor progression, while miR-135a-5p exerted inhibitory effects on NSCLC development. This study offers a novel perspective for researchers to elucidate functional disparities exhibited by highly homologous miRNAs (miR-135a-5p and miR-135b-5p) in the context of NSCLC, along with the transition from inhibitory to progressive states in NSCLC. This study provides a solid foundation for future investigations into the functional roles of highly homologous miRNAs in pathological situation.

高度同源的 miR-135a 和 miR-135b 通过增强子转换将非小细胞肺癌从抑制转为进展。
微小核糖核酸(miRNA)是一种短小的非编码核糖核酸,因其在癌症进展中的重要作用而被越来越多的人所认识。不同的 miRNA 因其序列的变化而表现出不同的功能。由于具有高度同源的种子序列,这些 miRNA 以重叠或相似的基因组为靶标,从而发挥类似的作用。然而,与这种观点不同的是,我们的研究发现,miR-135a-5p 和 miR-135b-5p 尽管只有一个核苷酸的差异,却表现出不同的功能作用。以非小细胞肺癌(NSCLC)为范例,我们的研究结果通过 TCGA 数据库揭示了 NSCLC 中 miR-135a-5p 的下调和 miR-135b-5p 的上调。因此,我们进一步研究了它们在 A549 细胞中的功能差异。miR-135b-5p的过表达增强了A549细胞的增殖和迁移能力,而miR-135a-5p转染则表现出相反的效果。我们证明,激活特定的增强子是 miR-135a-5p 和 miR-135b-5p 在 NSCLC 中发挥不同功能的关键机制,从而促使 NSCLC 的进展从抑制转向激活。最后,我们通过动物实验验证了 miR-135b-5p 能促进肿瘤进展,而 miR-135a-5p 对 NSCLC 的发展有抑制作用。这项研究为研究人员阐明高度同源的 miRNA(miR-135a-5p 和 miR-135b-5p)在 NSCLC 中表现出的功能差异,以及 NSCLC 从抑制状态到进展状态的转变提供了一个新的视角。这项研究为今后研究高度同源 miRNA 在病理情况下的功能作用奠定了坚实的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human molecular genetics
Human molecular genetics 生物-生化与分子生物学
CiteScore
6.90
自引率
2.90%
发文量
294
审稿时长
2-4 weeks
期刊介绍: Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.
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